Rhodium-catalyzed decarboxylative cycloaddition route to substituted anilines

Article abstract of DOI:10.1021/jo200236h

A convenient method for preparing substituted anilines via a Rh-catalyzed [2 + 2 + 2] cycloaddition reaction of diynes and 2-oxazolone was discovered. The initial cycloaddition adducts undergo facile decarboxylation of carbon dioxide to afford aniline products. Reaction conditions are mild, and only 3 mol % Rh catalyst is required. High regioselectivity was observed when an unsymmetrical diyne was used as a starting material.

Full text of DOI:10.1021/jo200236h

NOTE
pubs.acs.org/joc
Rhodium-Catalyzed Decarboxylative Cycloaddition Route to
Substituted Anilines
Kainan Zhang and Janis Louie*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112-0850, United States
S Supporting Information
b
ABSTRACT: A convenient method for preparing substituted
anilines via a Rh-catalyzed [2 þ 2 þ 2] cycloaddition reaction of
diynes and 2-oxazolone was discovered. The initial cycloaddition
adducts undergo facile decarboxylation of carbon dioxide to
afford aniline products. Reaction conditions are mild, and only 3
mol % Rh catalyst is required. High regioselectivity was observed
when an unsymmetrical diyne was used as a starting material.
ubstituted anilines are important structural motifs that are
found in a variety of natural products, biologically active
S
compounds, and agrochemicals.1 As such, efficient methods for
the synthesis of substituted anilines are highly desirable.
Although a variety of procedures that generate substituted
anilines exist,2 [2 þ 2 þ 2] cycloaddition routes are rare.3 The
lack of cycloaddition routes could be due to the lack of suitable
nitrogen-containing starting materials that can undergo cycload-
dition chemistry.4 One such starting material is the ynamide.5
For example, both the Hsung group6 and the Tanaka group7 have
reported the use of ynamides in the enantioselective preparation
of axially chiral anilides through a rhodium-catalyzed [2 þ 2 þ 2]
cycloaddition. We have been interested in expanding the reper-
toire of cycloaddition chemistry8 to include other readily avail-
able nitrogen-containing starting materials. Herein we report our
findings that demonstrate that 2-oxazolones can be used as
substrates in [2 þ 2 þ 2] cycloaddition chemistry. These
cycloadditions afford substituted anilines through spontaneous
decarboxylation of the initial cycloaddition product.
Table 1. Rh-Catalyzed Cycloadditions of Diyne and
2-Oxazolonea
entry
metal source
ligands
conversionb (%) yieldb (%)
1
[Rh(COD)2]BF4 BINAP
>99
>99
79
>99
80
83
0
2
[Rh(COD)2]BF4 (S)-H8-BINAP
[Rh(COD)2]BF4 dppf
3
4
[Rh(COD)2]BF4 dppe
69
5c
6c
Ni(COD)2
IMes
12
0
Ni(COD)2
IPr
21
0
a 10 mol % [Rh(COD)2]BF4 (0.01 M), 10 mol % ligand (0.01 M), 1
(0.1M), 4(0.5M) inTHFat60°C. b Conversions of diyne 1and yields of 5
were determined by GC with naphthalene as an internal standard. c 10 mol %
Ni(COD)2 (0.01 M), 20 mol % ligand (0.02 M) in THF at 60 °C.
ligand, these systems still gave substantially lower product yields
than the parent BINAP system (entries 2 and 3). Interestingly,
no product was observed when a slightly different bidentate
phosphine (i.e., dppe) was used (entry 4). Our group has had
success employing a combination of Ni(0) and N-heterocyclic
carbene ligands as catalysts for a variety of [2 þ 2 þ 2]
cycloadditions.8 However, the Ni/NHC system was not an
effective catalyst system for either the [2 þ 2 þ 2] cycloaddition
of diyne 1 and either vinylene carbonate 2 or 2-oxazolone 4
(entries 5 and 6).
Tanaka and co-workers reported the Rh(I)/BINAP-catalyzed
[2 þ 2 þ 2] cycloaddition of diyne 1 and vinylene carbonate 2 to
synthesize a phenol derivative 3 through elimination of carbon
dioxide (eq 1).9 Inspired by Tanaka’s work,10 we investigated
whether 2-oxazolones could be used instead of vinylene carbo-
nates. Thus, the [2 þ 2 þ 2] cycloaddition of 1,6-diyne 1 and
2-oxazolone 411 (5 equiv) was examined in the presence of 10
mol % cationic rhodium(I)/BINAP at 60 °C (eq 2, Table 1).
Gratifyingly, the desired aniline product was obtained in
excellent yield (as determined by GC). Other bidentate phos-
phines were also evaluated. Although good yields of aniline were
formed when either (S)-H8-BINAP or dppf were used as the
The reaction conditions were further optimized (Table 2).
The catalyst loading could be reduced from 5 to 3 mol % with
little effect on the GC yields (Table 2, entries 1ꢀ3). Importantly,
Received: February 24, 2011
Published: April 14, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo200236h J. Org. Chem. 2011, 76, 4686–4691
|

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NOTE
Table 2. Various Rh-Catalyzed Cycloaddition Conditionsa
the concentration of 2-oxazolone 4 could be substantially
reduced to only 1 equiv without compromising product yield
(entries 2, 4ꢀ6). Although the reaction proceeds at lower
temperatures, lower product yields were observed (entries 7 and 8).
Thus, our optimized reaction conditions utilized 3 mol %
[Rh(COD)2]BF4, 3 mol % BINAP, 0.1 M diyne, and 0.1 M
2-oxazolone in THF at 60 °C.
[Rh(COD)2]BF4
(mol %)
BINAP
entry
(mol %)
4 (M)
T (°C)
yieldb (%)
1
2
3
4
5
6
7
8
5
3
1
3
3
3
3
3
5
3
1
3
3
3
3
3
0.5
0.5
0.5
0.3
0.15
0.1
0.1
0.1
60
60
60
60
60
60
40
rt
>99
95
25
A variety of diynes were subjected to the optimized Rh-
catalyzed [2 þ 2 þ 2] cycloaddition reactions described above
(Table 3). In addition to the standard diyne (1), more flexible
diynes such as diyne 6, ether diyne 8, and N-sulfonamide diyne
10 were converted to their respective anilines (7, 9, and 11) in
good yields (entries 1ꢀ4). Similarly, highly oxygenated diynes
such as 12 and 14 afforded good yields of cyclotrimerized
products (entries 5ꢀ7). Interestingly, diynes prone to
homodimerization12 (i.e., terminal diynes 1813 and 30 as well
as phenyl-substituted diyne 20) could also be used as cycloaddi-
tion substrates (entries 8, 9, and 14), although some homo-
dimerization was still observed. However, the phenyl-substituted
diyne afforded the aniline product in substantially higher
yield than its terminal diyne analogue. The cycloaddition
was somewhat tolerant to steric hindrance on the diyne. For
example, diyne 22 that possesses i-Pr groups was converted
aniline 13, albeit in lower yield (entry 10). A similar yield was
obtained when cyano groups were present on the diyne (24,
entry 11). Despite the low aniline yield, no pyridine products
were observed in this reaction.14 Diyne 26 bearing two phenyl
sulfones was converted to aniline product 27 inexcellent 99% yield
(entry 12). In addition, a diyne possessing a four atom linker
instead of a three atom linker (diynes 28 and 30) were effectively
converted to their respective anilines 29 and 31 in good yield
(entries 13 and 14).
>99
>99
>99
83
73
a 1 (0.1 M) in THF at 60 °C. b Determined by GC with naphthalene as
an internal standard.
Table 3. Decarboxylative Rh-Catalyzed [2 þ 2 þ 2]
`Cycloadditions with 2-Oxazolone 4a
Unsymmetrical diyne 32 was also evaluated under these
reaction conditions (eq 3). Surprisingly, high regioselectivity
was observed in the cycloaddition reaction, and aniline derivative
33 was the only observed product.15 Selective insertion of the
oxazolone, possibly due to initial binding of the nitrogen or the
polarized nature of the double bond, may account for the
regioselectivity observed (Scheme 1).
Scheme 1. Possible Mechanism for Regioselective Oxazo-
lone Insertion
N-Acetyl-2-oxazolone 34 was also examined as a potential
substrate in the Rh-catalyzed cycloaddition reactions. The reac-
tion of 34 with diyne 1 afforded a mixture of three products
(eq 4). Diyne dimerization product 35 was the major product.
Only trace amounts of the corresponding acetyl-protected
a 3 mol % [Rh(COD)2]BF4 (0.003 M), 3 mol % BINAP (0.003 M),
diyne (0.1 M), and 2-oxazolone (0.1 M) in THF at 60 °C for 6 h.
b Isolated yields (average of two runs).
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NOTE
aniline 36 was detected by GCꢀMS. Aniline 5 was isolated in
THF (153 mL) was added bis(phenylsulfonyl)methane (2.780 g, 6.940
mmol) dropwise via a disposable syringe at 0 °C. The reaction mixture
was stirred for 30 min until it became clear, and then 1-bromo-but-2-yne
(2.03 g, 15.3 mmol) was added dropwise via a disposable syringe. The
reaction was refluxed for 40 h and then quenched by cold saturated
ammonium chloride solution. The aqueous layer was extracted 3 ꢁ
50 mL with diethyl ether. The organic layer was combined, dried over
sodium sulfate, and concentrated under vacuum to give crude product
26. Purification by flash column chromatography (20% diethyl ether/
pentane) yielded pure product 26 (1.84 g, 49%) as a yellow powder. Rf =
0.30 (20% diethyl ether/pentane). Mp: 140ꢀ142 °C. 1H NMR
(300 MHz, CDCl3, ppm): δ 8.20 (d, J = 7.5 Hz, 4H), 7.70 (t, J = 7.2 Hz,
2H), 7.58 (t, J = 7.8 Hz, 4H), 3.16 (d, J = 2.7 Hz, 4H), 1.76 (t, J = 1.8 Hz,
2H). 13C NMR (75 MHz, CDCl3, ppm): δ 137.1, 135.0, 131.9, 128.7,
88.2, 82.2, 70.8, 21.6, 4.2. IR (CH2Cl2, cmꢀ1): 3067, 2920, 2254, 1448,
1335, 1314, 1149, 1078, 912. HRMS (ESI) calcd for C21H20O4S2Na
[M þ Na]þ: 423.0701, found 423.0706.
10% yield from this reaction.
In summary, we have developed a new method to synthe-
size highly functionalized bicyclic aniline derivatives via
[Rh(COD)2]BF4/BINAP-catalyzed [2 þ 2 þ 2] cycloaddition
reactions of diynes and 2-oxazolone. When unsymmetrical
diynes were used, high regioselectivities were observed. Further
exploration of this methodology is underway.
’ EXPERIMENTAL SECTION
Dimethyl 2,2-di(but-2-yn-1-yl)malonate (1),16 methyl 2-(but-2-yn-1-
yl)hex-4-ynoate (6),17 5,5-di(but-2-yn-1-yl)-2,2-dimethyl-1,3-dioxane
(12),18 1-(but-2-yn-1-yloxy)but-2-yne (8),8c (((2,2-di(but-2-yn-1-yl)-
propane-1,3-diyl)bis(oxy))bis(methylene)]dibenzene (16),8c dimethyl
2,2-di(prop-2-yn-1-yl)malonate (18),19 dimethyl 2,2-bis(3-phenylprop-
2-yn-1-yl)malonate (20),20 dimethyl 2,2-bis(4-methylpent-2-yn-1-
yl)malonate (22),8c 2,2-di(but-2-yn-1-yl)malononitrile (24),21 (nona-
2,7-diyne-5,5-diyldisulfonyl)dibenzene (26),22 tetraethyl deca-2,8-diyne-
5,5,6,6-tetracarboxylate (28),8a and tetraethyl octa-1,7-diyne-4,4,5,5-
tetracarboxylate (30)23 were prepared according to literature procedures.
2-Oxazolone (4) and N-acetyl-2-oxazolone were prepared according to
literature procedures.24
5,5-Di(but-2-yn-1-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione
(14). To a suspended solution of sodium hydride (366 mg, 15.3 mmol,
0.1 M) in THF (153 mL) was added 2,2-dimethyl-1,3-dioxane-4,6-dione
(1.000 g, 6.940 mmol) dropwise via a disposable syringe at 0 °C. The
reaction mixture was stirred for 30 min until it became clear, and then
1-bromo-but-2-yne (2.030 g, 15.30 mmol) was added dropwise via a
disposable syringe. The reaction was refluxed for 40 h and then
quenched by cold saturated ammonium chloride solution. The aqueous
layer was extracted 3 ꢁ 50 mL with diethyl ether. The organic layer was
combined, dried over sodium sulfate, and concentrated under vacuum to
give crude product 14. Purification by flash column chromatography
(20% diethyl ether/pentane) yielded pure product 14 (1.24 g, 72%) as a
white powder. Rf = 0.45 (20% diethyl ether/pentane). Mp: 153ꢀ154 °C.
1H NMR (500 MHz, CDCl3, ppm): δ 2.76 (q, J = 2 Hz, 4H), 1.81
(s, 6H), 1.73 (t, J = 1.2 Hz, 6H). 13C NMR (125 MHz, CDCl3, ppm):
δ 168.2, 106.9, 81.1, 73.0, 54.8, 30.1, 28.7, 3.8. IR (CH2Cl2, cmꢀ1):
3486, 2923, 1773, 1740, 1359, 1268, 1112, 1053, 958. HRMS (ESI) calcd
for C14H16O4Na [M þ Na]þ: 271.0946, found 271.0953.
2-But-2-ynyl-2,3-bis-ethoxycarbonyl-3-prop-2-ynyl-suc-
cinic Acid Diethyl Ester (32). To a suspended solution of sodium
hydride (366 mg, 15.3 mmol, 0.1 M) in THF (153 mL) was added
monoalkyne8d (5.15 g, 13.9 mmol) dropwise via a disposable syringe at
0 °C. The reaction mixture was stirred for 30 min until it became clear,
and then propargyl bromide (2.03 g, 15.3 mmol) was added dropwise
via a disposable syringe. The reaction was refluxed for 40 h and then
quenched by cold saturated ammonium chloride solution. The aqueous
layer was extracted 3 ꢁ 50 mL with diethyl ether. The organic layer was
combined, dried over sodium sulfate, and concentrated under vacuum to
give crude product 32. Purification by flash column chromatography
(20% diethyl ether/pentane) yielded pure product 32 (4.88 g, 86%) as a
white powder. Rf = 0.40 (20% diethyl ether/pentane). Mp: 55ꢀ56 °C.
1H NMR (500 MHz, CDCl3, ppm): δ 4.17ꢀ4.31 (m, 8H), 3.19 (d, J = 3
Hz, 2H), 3.04 (d, J = 2.5 Hz, 2H), 2.01 (s, 1H), 1.74 (t, J = 2.5 Hz, 3H),
1.29 (t, J = 7 Hz, 12H), 2.04 (s, 3H). 13C NMR (125 MHz, CDCl3,
ppm): δ 169.0, 168.8, 80.4, 78.8, 74.7, 70.9, 62.3, 62.2, 61.9, 61.8, 23.2,
22.7, 14.2, 4.0. IR (CH2Cl2, cmꢀ1): 3276, 2985, 1736, 1446, 1368, 1208,
1096, 1038, 864. HRMS (ESI) calcd for C21H28O8Na [M þ Na]þ:
431.1682, found 431.1681.
General Procedure for Rh-Catalyzed Cycloaddition Reac-
tion. In a glovebox, diyne (1 equiv) and 2-oxazolone (1 equiv) were
directly weighed into a scintillation vial equipped with a stir bar. A
catalyst stock solution was prepared by dissolution of [Rh(COD)2]BF4
(5.0 mg, 0.012 mmol, 0.0030 M) and BINAP (7.7 mg, 0.012 mmol,
0.0030 M) in THF (4.1 mL). To the scintillation vial containing
diyne and 2-oxazolone was added an aliquot of catalyst stock
solution. The scintillation vial was sealed, brought out of the box,
and heated for 6 h at 60 °C. The solvent was removed under vacuum,
(Nona-2,7-diyne-5,5-diyldisulfonyl)dibenzene (26). To a
suspended solution of sodium hydride (366 mg, 15.3 mmol, 0.1 M) in
4688
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NOTE
and the crude product was purified by flash column chromatography on
silica gel.
was used with diyne 12 (25.0 mg, 0.11 mmol, 0.1 M), 2-oxazolone 4
(9.7 mg, 0.11 mmol, 0.1 M), and a 1.1 mL aliquot of the
[Rh(COD)2]BF4/BINAP-catalyst stock solution in THF (1.1 mL total
volume) at 60 °C for 6 h. The reaction mixture was purified by flash
column chromatography on silica gel (60% diethyl ether/pentane) to
afford 13 (23.7 mg, 80% first run, 25.5 mg, 86% second run) as a white
Dimethyl 5-Amino-4,7-dimethyl-1H-indene-2,2(3H)-di-
carboxylate (5). The general cycloaddition procedure was used with
diyne 1 (20.0 mg, 0.085 mmol, 0.1 M), 2-oxazolone 4 (7.2 mg, 0.85
mmol, 0.1 M), and a 0.85 mL aliquot of the [Rh(COD)2]BF4/BINAP-
catalyst stock solution in THF (0.85 mL total volume) at 60 °C for 6 h.
The reaction mixture was purified by flash column chromatography on
silica gel (50% diethyl ether/pentane) to afford 5 (20.9 mg, 89%
first run, 19.0 mg, 81% second run) as a light yellow solid. Rf = 0.45
1
solid. Rf = 0.30 (60% diethyl ether/pentane). Mp: 147ꢀ148 °C. H
NMR (500 MHz, CDCl3, ppm): δ 6.40 (s, 1H), 3.78 (d, J = 11.1 Hz,
2H), 3.75 (d, J = 11.0 Hz, 2H), 3.47 (s, 2H), 2.83 (s, 2H), 2.73 (s, 3H),
2.14 (s, 3H), 2.04 (s, 3H), 1.49 (s, 6H). 13C NMR (125 MHz, CDCl3,
ppm): δ 143.7, 141.2, 132.4, 130.4, 116.4, 115.3, 105.3, 98.2, 69.7, 41.5,
40.0, 38.9, 24.6, 23.9, 19.1, 13.5. IR (CH2Cl2, cmꢀ1): 3452, 3362, 2991,
2936, 2856, 1625, 1499, 1453, 1381, 1246, 1198, 1154, 1096, 831.
HRMS (ESI) calcd for C16H24NO2 [M þ H]þ: 262.1807, found
262.1798.
1
(50% diethyl ether/pentane). Mp: 96ꢀ98 °C. H NMR (500 MHz,
CDCl3, ppm): δ 6.39 (s, 1H), 3.76 (s, 6H), 3.53 (s, 2H), 3.47 (brs, 2H),
3.46 (s, 2H), 2.14 (s, 3H), 2.04 (s, 3H). 13C NMR (125 MHz, CDCl3,
ppm): δ 172.8, 144.1, 139.7, 131.7, 129.0, 115.8, 60.1, 53.2, 40.4, 39.6,
19.0, 13.5. IR (CH2Cl2, cmꢀ1): 3377, 2954, 1733, 1627, 1434, 1263,
1198, 1163. HRMS (ESI) calcd for C15H20NO4 [M þ H]þ: 278.1389,
found 278.1392.
50-Amino-2,2,40,70-tetramethyl-10,30-dihydrospiro[[1,3]dio-
xane-5,20-indene]-4,6-dione (15). The general cycloaddition pro-
cedure was used with diyne 14 (25.0 mg, 0.10 mmol, 0.1 M),
2-oxazolone 4 (8.8 mg, 0.10 mmol, 0.1 M), and a 1.0 mL aliquot of
the [Rh(COD)2]BF4/BINAP-catalyst stock solution in THF (1.0 mL
total volume) at 60 °C for 6 h. The reaction mixture was purified by flash
column chromatography on silica gel (80% diethyl ether/pentane) to
afford 15 (21.3 mg, 73% first run, 20.7 mg, 71% second run) as a light
yellow solid. Rf = 0.38 (20% diethyl ether/pentane). Mp: 177ꢀ178 °C.
1H NMR (500 MHz, CDCl3, ppm): δ 6.42 (s, 1H), 3.64 (s, 2H), 3.54
(s, 2H), 3.51 (s, 2H), 2.12 (s, 3H), 2.02 (s, 3H), 1.83 (s, 3H), 1.81 (s, 3H).
13C NMR (125 MHz, CDCl3, ppm): δ 171.3, 144.7, 139.0, 131.5, 127.7,
116.4, 115.4, 105.3, 52.4, 45.3, 29.3, 19.1, 13.6. IR (CH2Cl2, cmꢀ1):
3386, 2932, 1765, 1732, 1628, 1385, 1284, 1202, 1045, 949, 734. HRMS
(ESI) calcd for C16H19NO4Na [M þ Na]þ: 312.1212, found 312.1218.
2,2-Bis((benzyloxy)methyl)-4,7-dimethyl-2,3-dihydro-1H-
inden-5-amine (17). The general cycloaddition procedure was used
with diyne 16 (25.0 mg, 0.069 mmol, 0.1 M), 2-oxazolone 4 (5.9 mg,
0.069 mmol, 0.1 M), and a 0.69 mL aliquot of the [Rh(COD)2]BF4/
BINAP-catalyst stock solution in THF (0.69 mL total volume) at 60 °C
for 6 h. The reaction mixture was purified by flash column chromatog-
raphy on silica gel (60% diethyl ether/pentane) to afford 17 (20.1 mg,
72% first run, 20.1 mg, 72% second run) as a white solid. Rf = 0.40 (60%
diethyl ether/pentane). Mp: 120ꢀ122 °C. 1H NMR (500 MHz, CDCl3,
ppm): δ 7.28ꢀ7.33 (m, 10H), 6.38 (s, 1H), 4.54 (s, 4H), 3.53 (s, 4H),
3.44 (s, 2H), 2.79 (s, 2H), 2.72 (s, 2H), 2.11 (s, 3H), 2.01 (s, 3H). 13C
NMR (125 MHz, CDCl3, ppm): δ 143.4, 141.9, 139.2, 132.2, 131.3,
128.6, 127.8, 127.7, 116.4, 115.1, 74.2, 73.5, 47.8, 39.0, 38.1, 19.1, 16.4,
13.5. IR (CH2Cl2, cmꢀ1): 3366, 2858, 1621, 1498, 1361, 1104, 731.
HRMS (ESI) calcd for C27H31NO2Na [M þ Na]þ: 424.2252, found
424.2254.
Methyl 5-Amino-4,7-dimethyl-2,3-dihydro-1H-indene-2-
carboxylate (7). The general cycloaddition procedure was used with
diyne 6 (25.0 mg, 0.140 mmol, 0.1 M), 2-oxazolone 4 (11.9 mg, 0.140
mmol, 0.1 M), and a 1.4 mL aliquot of the [Rh(COD)2]BF4/BINAP-
catalyst stock solution in THF (1.4 mL total volume) at 60 °C for 6 h.
The reaction mixture was purified by flash column chromatography on
silica gel (60% diethyl ether/pentane) to afford 7 (23.7 mg, 77% first
run, 24.3 mg, 79% second run) as a yellow solid. Rf = 0.52 (60% diethyl
1
ether/pentane). Mp: 86ꢀ88 °C. H NMR (400 MHz, CDCl3, ppm):
δ 6.40 (s, 1H), 3.74 (s, 3H), 3.48 (s, 2H), 3.32 (dd, J = 17.3 Hz, 8.7 Hz,
1H), 3.07ꢀ3.17 (m, 4H), 2.15 (s, 3H), 2.05 (s, 3H). 13C NMR
(100 MHz, CDCl3, ppm): δ 176.5, 143.8, 141.4, 131.8, 130.6, 115.9,
115.3, 52.2, 43.3, 35.8, 35.0, 19.1, 13.5. IR (CH2Cl2, cmꢀ1): 3382, 2947,
2851, 1724, 1626, 1500, 1435, 1362, 1266, 1206, 1165. HRMS (ESI)
calcd for C13H18NO2 [M þ H]þ: 220.1338, found 220.1332.
4,7-Dimethyl-1,3-dihydroisobenzofuran-5-amine (9). The
general cycloaddition procedure was used with diyne 8 (25.0 mg, 0.21
mmol, 0.1 M), 2-oxazolone 4 (17.4 mg, 0.21 mmol, 0.1 M), and a 2.1 mL
aliquot of the [Rh(COD)2]BF4/BINAP-catalyst stock solution in THF
(2.1 mL total volume) at 60 °C for 6 h. The reaction mixture was purified
by flash column chromatography on silica gel (75% diethyl ether/
pentane) to afford 9 (21.0 mg, 63% first run, 23.7 mg, 71% second run)
as a yellow solid. Rf = 0.32 (75% diethyl ether/pentane). Mp:
1
120ꢀ122 °C. H NMR (500 MHz, CDCl3, ppm): δ 6.44 (s, 1H),
5.08 (s, 2H), 5.04 (s, 2H), 3.56 (s, 2H), 2.13 (s, 3H), 2.01 (s, 3H). 13C
NMR (125 MHz, CDCl3, ppm): δ 144.4, 139.2, 129.4, 128.2, 115.8,
113.0, 74.0, 73.9, 18.8, 13.6. IR (CH2Cl2, cmꢀ1): 3466, 3360, 3232,
2846, 1635, 1503, 1370, 1303, 1048, 896, 852. HRMS (ESI) calcd for
C10H14NO [M þ H]þ: 164.1075, found 164.1054.
Dimethyl 5-Amino-1H-indene-2,2(3H)-dicarboxylate (19).
The general cycloaddition procedure was used with diyne 18 (25.0 mg,
0.120 mmol, 0.1 M), 2-oxazolone 4 (10.2 mg, 0.120 mmol, 0.1 M), and a
1.2 mL aliquot of the [Rh(COD)2]BF4/BINAP-catalyst stock solution
in THF (1.2 mL total volume) at 60 °C for 6 h. The reaction mixture was
purified by flash column chromatography on silica gel (75% diethyl
ether/pentane) to afford 19 (8.6 mg, 29% first run, 9.3 mg, 31% second
run) as a white solid. Rf = 0.30 (75% diethyl ether/pentane). Mp:
84ꢀ86 °C. 1H NMR (300 MHz, CDCl3, ppm): δ 6.96 (d, J = 7.8 Hz,
2H), 6.54 (s, 1H), 6.51 (d, J = 8.4 Hz, 2H), 3.73 (s, 6H), 3.55 (br, 2H),
3.50 (s, 2H), 3.48 (s, 2H). 13C NMR (125 MHz, CDCl3, ppm): δ 172.6,
145.9, 141.5, 130.1, 125.1, 114.5, 111.3, 61.0, 53.3, 40.9, 40.2. IR
(CH2Cl2, cmꢀ1): 3376, 2955, 1732, 1626, 1499, 1435, 1253, 1200,
1067. HRMS (ESI) calcd for C13H16NO4 [M þ H]þ: 250.1079, found
250.1071.
4,7-Dimethyl-2-tosylisoindolin-5-amine (11). The general
cycloaddition procedure was used with diyne 10 (20.0 mg, 0.073 mmol,
0.1 M), 2-oxazolone 4 (6.2 mg, 0.073 mmol, 0.1 M), and a 0.73 mL
aliquot of the [Rh(COD)2]BF4/BINAP-catalyst stock solution in THF
(0.73 mL total volume) at 60 °C for 6 h. The reaction mixture was
purified by flash column chromatography on silica gel (80% diethyl
ether/pentane) to afford 11 (19.3 mg, 84% first run, 20.7 mg, 90%
second run) as a white solid. Rf = 0.40 (80% diethyl ether/pentane). Mp:
198ꢀ200 °C. 1H NMR (300 MHz, CDCl3, ppm): δ 7.78 (d, J = 8.1 Hz,
2H), 7.31 (d, J = 8.1 Hz, 2H), 6.40 (s, 1H), 4.54 (s, 2H), 4.49 (s, 2H),
3.55 (s, 2H), 2.42 (s, 3H), 2.08 (s, 3H), 1.95 (s, 3H). 13C NMR
(125 MHz, CDCl3, ppm): δ 144.7, 143.8, 136.1, 134.1, 130.8, 130.1,
127.9, 125.1, 116.0, 114.1, 54.0, 53.6, 21.8, 18.7, 13.4. IR (CH2Cl2, cmꢀ1):
3378, 2922, 2853, 1631, 1506, 1462, 1339, 1162, 1099, 666. HRMS
(ESI) calcd for C17H20N2O2SNa [M þ Na]þ: 339.1143, found
339.1151.
Dimethyl 5-Amino-4,7-diphenyl-1H-indene-2,2(3H)-
dicarboxylate (21). The general cycloaddition procedure was
used with diyne 20 (25.0 mg, 0.063 mmol, 0.1 M), 2-oxazolone 4
2,2,40,70-Tetramethyl-10,30-dihydrospiro[[1,3]dioxane-
5,20-inden]-50-amine (13). The general cycloaddition procedure
4689
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The Journal of Organic Chemistry
NOTE
(5.9 mg, 0.063 mmol, 0.1 M), and a 0.66 mL aliquot of the [Rh(COD)2]-
BF4/BINAP-catalyst stock solution in THF (0.66 mL total volume) at
60 °C for 6 h. The reaction mixture was purified by flash column
chromatography on silica gel (60% diethyl ether/pentane) to afford 21
(22.6 mg, 81% first run, 24.2 mg, 87% second run) as a white solid. Rf =
0.60 (60% diethyl ether/pentane). Mp: 56ꢀ58 °C. 1H NMR (300 MHz,
CDCl3, ppm): δ 7.34ꢀ7.49 (m, 10H), 6.69 (s, 1H), 3.68 (s, 6H), 3.62
(s, 2H), 3.60 (brs, 2H), 3.36 (s, 2H). 13C NMR (75 MHz, CDCl3, ppm):
δ 172.5, 143.7, 141.1, 140.6, 138.4, 137.4, 129.9, 129.5, 128.7, 127.8,
127.6, 127.4, 123.8, 115.3, 60.7, 53.2, 40.7, 40.4. IR (CH2Cl2, cmꢀ1):
3381, 2953, 1734, 1650, 1475, 1435, 1249, 1201, 1164, 1072. HRMS
(ESI) calcd for C25H24NO4 [M þ H]þ: 402.1705, found 402.1700.
Dimethyl 5-Amino-4,7-diisopropyl-1H-indene-2,2(3H)-di-
carboxylate (23). The general cycloaddition procedure was used with
diyne 22 (25.0 mg, 0.086 mmol, 0.1 M), 2-oxazolone 4 (7.3 mg, 0.086
mmol, 0.1 M), and a 0.86 mL aliquot of the [Rh(COD)2]BF4/BINAP-
catalyst stock solution in THF (0.86 mL total volume) at 60 °C for 6 h.
The reaction mixture was purified by flash column chromatography on
silica gel (50% diethyl ether/pentane) to afford 23 (11.7 mg, 41% first
run, 10.5 mg, 37% second run) as a light yellow oil. Rf = 0.55 (50%
column chromatography on silica gel (70% diethyl ether/pentane) to
afford 29 (20.8 mg, 76% first run, 22.5 mg, 82% second run) as a light
yellow solid. Rf = 0.28 (70% diethyl ether/pentane). Mp: 92ꢀ94 °C. 1H
NMR (300 MHz, CDCl3, ppm): δ 6.42 (s, 1H), 4.10ꢀ4.28 (m, 8H),
3.42 (brs, 2H), 3.38 (s, 2H), 3.29 (s, 2H), 2.13 (s, 3H), 2.02 (s, 3H), 1.21
(t, J = 6.9 Hz, 12H). 13C NMR (75 MHz, CDCl3, ppm): δ 170.5, 142.2,
133.7, 131.7, 122.1, 117.5, 116.2, 61.9, 57.6, 57.3, 33.5, 32.4, 19.8, 14.0,
12.4. IR (CH2Cl2, cmꢀ1): 3379, 2983, 1734, 1627, 1478, 1444, 1389,
1263, 1204, 1095, 1051. HRMS (ESI) calcd for C24H33NO8Na
[M þ Na]þ: 486.2104, found 486.2104.
Tetraethyl 6-Aminonaphthalene-2,2,3,3(1H,4H)-tetracar-
boxylate (31). The general cycloaddition procedure was used with
diyne 30 (30.0 mg, 0.076 mmol, 0.1 M), 2-oxazolone 4 (6.5 mg, 0.076
mmol, 0.1 M), and a 0.76 mL aliquot of the [Rh(COD)2]BF4/BINAP-
catalyst stock solution in THF (0.76 mL total volume) at 60 °C for 6 h.
The reaction mixture was purified by flash column chromatography on
silica gel (30% diethyl ether/pentane) to afford 31 (12.6 mg, 38% first
run, 14.6 mg, 44% second run) as a light yellow oil. Rf = 0.30 (30%
diethyl ether/pentane). 1H NMR (500 MHz, CDCl3, ppm): δ 6.86 (d,
J = 7.5Hz, 1H), 6.47 (d, J = 7.5 Hz, 1H), 6.41 (s, 1H), 4.13ꢀ4.25 (m, 8H),
3.48 (brs, 2H), 3.42 (s, 2H), 3.40 (s, 2H), 1.22 (td, J = 7.1 Hz, 3.4 Hz,
12H). 13C NMR (125 MHz, CDCl3, ppm): δ 170.3, 144.7, 133.8,
129.4, 123.2, 114.7, 114.4, 62.1, 62.0, 58.0, 57.8, 35.8, 34.3, 14.1. IR
(CH2Cl2, cmꢀ1): 3455, 3378, 2983, 1734, 1625, 1512, 1444, 1367,
1265, 1201, 1095, 1039. HRMS (ESI) calcd for C22H29NO8Na
[M þ Na]þ: 458.1791, found 458.1788.
1
diethyl ether/pentane). H NMR (300 MHz, CDCl3, ppm): δ 6.47
(s, 1H), 3.74 (s, 6H), 3.59 (s, 2H), 3.56 (brs, 2H), 3.46 (s, 2H). 3.10
(dt, J = 14.4 Hz, 7.2 Hz, 1H), 2.84 (dt, J = 13.8 Hz, 6.9 Hz, 1H), 1.32
(d, 7.2 Hz, 6H), 1.18 (d, 6.9 Hz, 6H). 13C NMR (75 MHz, CDCl3,
ppm): δ 172.7, 143.6, 142.6, 138.9, 128.9, 126.1, 113.2, 60.6, 53.2, 40.8,
38.3, 30.9, 28.6, 23.1, 21.0. IR (CH2Cl2, cmꢀ1): 2959, 1735, 1626, 1431,
1250, 1201, 1167. HRMS (ESI) calcd for C19H28NO4 [M þ H]þ:
334.2018, found 334.2013.
Tetraethyl 6-Amino-5-methylnaphthalene-2,2,3,3(1H,4H)-
tetracarboxylate (33). The general cycloaddition procedure was
used with diyne 32 (25.0 mg, 0.061 mmol, 0.1 M), 2-oxazolone 4 (5.3
mg, 0.061 mmol, 0.1 M), and a 0.61 mL aliquot of the [Rh(COD)2]-
BF4/BINAP-catalyst stock solution in THF (0.61 mL total volume) at
60 °C for 6 h. The reaction mixture was purified by flash column
chromatography on silica gel (70% diethyl ether/pentane) to afford 33
(12.1 mg, 44% first run, 13.8 mg, 50% second run) as a colorless oil.
5-Amino-4,7-dimethyl-1H-indene-2,2(3H)-dicarbonitrile
(25). The general cycloaddition procedure was used with diyne 24
(30.0 mg, 0.18 mmol, 0.1 M), 2-oxazolone 4 (15.0 mg, 0.18 mmol, 0.1 M),
and a 1.8 mL aliquot of the [Rh(COD)2]BF4/BINAP-catalyst stock
solution in THF (1.8 mL total volume) at 60 °C for 6 h. The reaction
mixture was purified by flash column chromatography on silica gel (70%
diethyl ether/pentane) to afford 25 (15.3 mg, 41% first run, 13.0 mg,
35% second run) as a white solid. Rf = 0.45 (70% diethyl ether/pentane).
Mp: 176ꢀ178 °C. 1H NMR (500 MHz, CDCl3, ppm): δ 6.46 (s, 1H),
3.64 (s, 2H), 3.62 (s, 2H), 3.59 (s, 2H), 2.16 (s, 3H), 2.04 (s, 3H). 13C
NMR (125 MHz, CDCl3, ppm): δ 145.4, 136.2, 132.5, 125.0, 117.2,
116.7, 116.0, 44.5, 43.7, 33.5, 19.1, 13.7. IR (CH2Cl2, cmꢀ1): 3481,
3390, 3370, 2921, 1626, 1502, 1441, 1346, 1061, 1018, 855. HRMS
(ESI) calcd for C13H14N3 [M þ H]þ: 212.1188, found 212.1187.
4,7-Dimethyl-2,2-bis(phenylsulfonyl)-2,3-dihydro-1H-in-
den-5-amine (27). The general cycloaddition procedure was used
with diyne 26 (25.0 mg, 0.062 mmol, 0.1 M), 2-oxazolone 4 (5.4 mg,
0.062 mmol, 0.1 M), and a 0.62 mL aliquot of the [Rh(COD)2]-
BF4/BINAP-catalyst stock solution in THF (0.62 mL total volume) at
60 °C for 6 h. The reaction mixture was purified by flash column
chromatography on silica gel (50% diethyl ether/pentane) to afford 27
(27.0 mg, 98% first run, 27.6 mg, 100% second run) as a yellow solid. Rf =
0.50 (50% diethyl ether/pentane). Mp: dec >200 °C. 1H NMR
(500 MHz, CDCl3, ppm): δ 7.91 (d, J = 8.5 Hz, 4H), 7.58 (t, J = 7.5
Hz, 2H), 7.44 (t, J = 8.0 Hz, 4H), 6.19 (s, 1H), 4.00 (brs, 2H), 3.81
(s, 2H), 3.74 (s, 2H), 1.93 (s, 3H), 1.86 (s, 3H). 13C NMR (125 MHz,
CDCl3, ppm) δ: 143.1, 137.8, 137.3, 134.7, 131.3, 130.8, 130.6, 129.0,
128.8, 127.7, 116.5, 116.0, 115.7, 92.8, 38.2, 37.5, 18.8, 13.4. IR
(CH2Cl2, cmꢀ1): 3380, 2920, 1754, 1626, 1447, 1327, 1149, 1079. HRMS
(ESI) calcd for C23H23NO4S2Na [M þ Na]þ: 464.0966, found 464.0969.
Tetraethyl 6-Amino-5,8-dimethylnaphthalene-2,2,3,3-
(1H,4H)-tetracarboxylate (29). The general cycloaddition proce-
dure was used with diyne 28 (25.0 mg, 0.059 mmol, 0.1 M), 2-oxazolone
4 (5.0 mg, 0.059 mmol, 0.1 M), and a 0.59 mL aliquot of the
[Rh(COD)2]BF4/BINAP-catalyst stock solution in THF (0.59 mL total
volume) at 60 °C for 6 h. The reaction mixture was purified by flash
1
Rf = 0.20 (70% diethyl ether/pentane). H NMR (500 MHz, CDCl3,
ppm): δ 6.76 (d, J = 8 Hz, 1H), 6.53 (d, J = 7.5 Hz, 1H), 4.13ꢀ4.26
(m, 8H), 3.47 (s, 2H), 3.43 (s, 2H), 3.39 (s, 2H), 2.04 (s, 3H), 1.23
(dt, J = 10.7 Hz, 7.1 Hz, 12H). 13C NMR (125 MHz, CDCl3, ppm):
δ 170.6, 170.4, 142.8, 131.9, 126.6, 123.5, 120.0, 114.5, 62.1, 62.0, 58.1,
57.4, 34.9, 33.5, 14.1, 12.7. IR (CH2Cl2, cmꢀ1): 3453, 3379, 2983, 1734,
1627, 1491, 1444, 1367, 1266, 1204, 1096, 1047, 863. HRMS (ESI) calcd
for C23H31NO8Na [M þ Na]þ: 472.1947, found 472.1950.
’ ASSOCIATED CONTENT
Supporting Information. 1H NMR and 13C NMR spec-
S
b
tra for all compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: louie@chem.utah.edu.
’ ACKNOWLEDGMENT
We gratefully acknowledge Cephalon, Inc. for support of this
research. We also thank Puneet Kumar for initial synthesis of
diynes 14 and 16.
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